Comprehensive characterization of tumor therapeutic response with simultaneous mapping cell size, density, and transcytolemmal water exchange

Abstract

Early assessment of tumor therapeutic response is an important topic in precision medicine to optimize personalized treatment regimens and reduce unnecessary toxicity, cost, and delay. Although diffusion MRI (dMRI) has shown potential to address this need, its predictive accuracy is limited, likely due to its unspecific sensitivity to overall pathological changes. In this work, we propose a new quantitative dMRI-based method dubbed EXCHANGE (MRI of water Exchange, Confined and Hindered diffusion under Arbitrary Gradient waveform Encodings) for simultaneous mapping of cell size, cell density, and transcytolemmal water exchange. Such rich microstructural information comprehensively evaluates tumor pathologies at the cellular level. Validations using numerical simulations and in vitro cell experiments confirmed that the EXCHANGE method can accurately estimate mean cell size, density, and water exchange rate constants. The results from in vivo animal experiments show the potential of EXCHANGE for monitoring tumor treatment response. Finally, the EXCHANGE method was implemented in breast cancer patients with neoadjuvant chemotherapy, demonstrating its feasibility in assessing tumor therapeutic response in clinics. In summary, a new, quantitative dMRI-based EXCHANGE method was proposed to comprehensively characterize tumor microstructural properties at the cellular level, suggesting a unique means to monitor tumor treatment response in clinical practice.

Keywords: arbitrary gradient waveform; diffusion MRI; microstructural imaging; time-dependent diffusion; tumor response; water exchange.

Fig. 1

Schematic diagrams of the main studies in this work. (a). four different diffusion movements of water molecules in the intra- and extracellular spaces. (b). restricted-induce edge-enhancement effect. (c). the discretization of an arbitrary diffusion gradient waveform $G(t)$. $\tau$ is the time duration of each short pulse. N is the total number of short pulses. (d). treatment-induced microstructural variations in tumor tissues.

Fig. 2.

The heat maps related to the fitted error of three different DW-MRI-based microstructural imaging Methods (EXCHANGE, JOINT, and IMPULSED) on the numerical simulations.

Fig. 3.

Results from the IMPULSED, JOINT, and EXCHANGE models in the four groups of retrospective cell experiments in vitro. The shaded area indicates the STD of light-microscopy obtained cell sizes.

Fig. 4

The results for the intergroup comparisons of variations in tumor volume and individual microstructural parameters in retrospective animal experiments in vivo.

Fig. 5.

EXCHANGE-derived $k_{in}$ and $d$ mappings of the members in the treatment ($T\text{\#1}$ and $T\text{\#2}$) and control groups ($C\text{\#}1$ and $C\text{\#}2$), which are overlaid on the b0 image of the PGSE sequence.

Fig. 6.

Left columns: EXCHANGE-derived microstructural parameter mappings (overlaid on the b0 image of PGSE), including $k_{in}$, $d$, and $v_{in}$. Rightmost column: the statistical results of the fitted parameters within all ROI voxels.